The phosphatidylinositol-3-kinases superfamily comprises 4 different PI3K related lipid or protein kinases. Class I, II and III are lipid kinases that differ by virtue of their substrate specificities whereas class IV PI3Ks (also called PIKKs) are protein kinases. Class I phosphatidylinositol-3-kinases comprise a family of lipid kinases that catalyze the transfer of phosphate to the D-3′ position of inositol lipids to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3) that, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane ((Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001)). Of the two Class I PI3Ks, Class IA PI3Ks are heterodimers composed of a catalytic p110 subunit (αβ, δ, isoforms) constitutively associated with a regulatory subunit that can be p85α, p55α, p50α, p85β or p55γ. The Class IB sub-class has one family member, a heterodimer composed of a catalytic p110γ subunit associated with one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)). The modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class IA PI3Ks. Class IB PI3K is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89:105 (1997)); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)). Consequently, the resultant phospholipid products of class 1 PI3K link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)).
In many cases, PIP2 and PIP3 recruit Akt, the product of the human homologue of the viral oncogene v-Akt, to the plasma membrane where it acts as a nodal point for many intracellular signaling pathways important for growth and survival (Fantl et al., Cell 69:413-423(1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2:489 (2002)). Aberrant regulation of PI3K, which often increases survival through Akt activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3′ position of the inositol ring and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the p110a isoform, PIK3CA, and for Aid are amplified and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85a that serve to up-regulate the p85-p110 complex have been described in human cancers. Also, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang et al., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations show that deregulation of phosphoinositol-3 kinase and the upstream and downstream components of this signaling pathway is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey et al., Nature Rev. Drug Disc. 4:988-1004 (2005)).
The mammalian target of rapamycin (mTOR) is a member of the class IV PI3K. mTOR assembles a signaling network that transduces nutrient signals and various other stimuli to regulate a wide range of cellular functions including cell growth, proliferation, survival, autophagy, various types of differentiation and metabolism. In mammalian cells, the mTOR protein is found complexed in two distinct entities called mTORC1 and mTORC2. The mTORC1 complex, that is to say mTOR associated with raptor, has been the matter of numerous studies. It is mTORC1 that integrates nutrient and growth factor inputs, and is in turn responsible for cell growth regulation, mainly through protein synthesis regulators such as 4EBP1 or RPS6. mTORC1 regulation requires PI3K and Akt activation for activation, meaning that mTORC1 is an effector of the PI3K pathway. mTOR when associated in the mTOR complex 2 (mTORC2) has been shown to be responsible for the activation of Akt by phosphorylation of S473 (Akt 1 numbering) (Sarbassov et al., Science 307:7098 (2005)). mTORC2 is hence here considered as an upstream activator of Akt. Interestingly mTOR can therefore be considered as being important both upstream and downstream of Akt. mTOR catalytic inhibiton might therefore represent a unique way of addressing a very strong block in the PI3K-Akt pathway, by addressing both upstream and downstream effectors.
A link between mTOR inhibition and autophagy has also been demonstrated (Ravikumar et al., Nat Genet. 36(6):585-95 (2004)). Autophagy is essential for neuronal homeostasis and its dysfunction has been linked to neurodegeneration. Loss of autophagy in neurons causes neurodegenerative disease in mice (Komatsu et al., Nature 441:880-4 (2006); Hara et al., Nature 441:885-9 (2006)) suggesting a critical role for autophagy to maintain protein homeostasis in neurons. Neurodegenerative diseases are characterized by inclusions of misfolded proteins as one of the hallmarks. Induction of autophagy enhances clearance of misfolded proteins and thus is proposed as therapy for neurodegenerative proteinopathies.
Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder where a mutation of IT15 gene encoding the Huntingtin (Htt) protein leads to Polyglutamine expansion in Exon1 of Htt. Intracellular aggregation of this mutant Htt protein and brain atrophy (in particular cortex and striatum) are the main hallmarks of HD. It clinically leads to movement disturbance and cognitive dysfunction besides psychiatric disturbances and weight loss.
Inhibition of mTOR induces autophagy and reduces mutant Htt aggregation and mutant Htt-mediated cell death in in vitro and in vivo models of HD (Ravikumar et al., Nat Genet. 36(6):585-95 (2004)). mTOR inhibition therefore provides an opportunity for pharmaceutical intervention and modulation of the disrupted cellular processes characteristic of HD.
In view of the above, mTOR inhibitors are considered to be of value in the treatment of proliferative diseases, such as cancer, and other disorders, in particular, HD.
The present invention relates to novel purine derivatives having mTOR inhibitory activity, their preparation, medical use and to medicaments comprising them.